Quantitative Optical Imaging of Molecular Processes in Preclinical Cancer Models

临床前癌症模型中分子过程的定量光学成像

• 批准号: 7894218
• 负责人: Walter John Akers
• 金额: $ 12.23万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-13 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894218
• 关键词: Affinity; Animal Model; Area; Award; Behavior; Biochemical; Biological; Biological Markers; Biomedical Research; Breast Cancer Model; Cancer Biology; Cancer Detection; Cancer Model; Cell Surface Receptors; Cells; Characteristics; Chemicals; Clinical; Comparative Pathology; Computer software; Contrast Media; Data; Decision Making; Detection; Development; Diagnosis; Diffusion; Diffusion weighted imaging; Disease model; Drug Kinetics; Early Diagnosis; Enzyme Kinetics; Enzymes; Fc Receptor; Fluorescence; Fluorescent Probes; Goals; Growth; Human; Image; Imaging Techniques; Injection of therapeutic agent; Instruction; Kinetics; Lead; Light; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary gland; Manuscripts; Measurement; Measures; Medicine; Mentors; Methods; Metric; Modality; Modeling; Molecular; Molecular Biology; Molecular Probes; Molecular Weight; Monitor; Monoclonal Antibodies; Multimodal Imaging; Mus; NIH Program Announcements; National Center for Research Resources; Optical Methods; Peptide Hydrolases; Peptides; Perfusion; Physiological; Physiology; Preclinical Drug Development; Procedures; Process; Proteins; Radioactive; Reporter; Research; Research Personnel; Research Training; Resistance; Signal Transduction; Speed; Techniques; Therapeutic; Therapeutic Effect; Tissues; Toxic effect; Training; Transgenic Organisms; Translating; Treatment Efficacy; Universities; Washington; Weight; Work; Writing; Xenograft procedure; base; bioimaging; career; career development; chemotherapy; clinical decision-making; cost; drug development; enzyme activity; experience; extracellular; imaging modality; improved; in vitro Assay; in vivo; intravenous injection; killings; macromolecule; malignant breast neoplasm; mathematical model; medical schools; molecular imaging; nanoparticle; neoplastic cell; optical imaging; outcome forecast; pharmacokinetic model; pre-clinical; protein aminoacid sequence; public health relevance; receptor binding; response; response marker; small molecule; therapeutic evaluation; tumor; water solubility

DESCRIPTION (provided by applicant): The application "Quantitative optical imaging of molecular processes in preclinical cancer models" is submitted in response to the NCRR program announcement for the Special Emphasis Research Career Award (SERCA, K01) in Pathology and Comparative Medicine. It is becoming increasingly evident that no single imaging modality is capable of providing sufficient information for diagnosis, prognosis and therapeutic efficacy. The Candidate seeks to gain training in biomedical imaging to lead an independent research career applying advanced optical imaging methods and magnetic resonance imaging (MRI) to investigate the molecular mechanisms of cancer. Areas of specific career development training will include courses covering molecular biology of cancer, principles of magnetic resonance imaging and principles of biomedical imaging and contrast agent development. Principles of molecular imaging using cancer-targeted fluorescent probes, including characteristics of contrast agents (small molecules, macromolecules and nanoparticles) and targeting moiety (monoclonal antibodies, receptor-specific proteins, high affinity peptides and cleavable peptide sequences).The Candidate will receive instruction on the physical and physiologic basis of Magnetic Resonance Imaging and the experimental procedures for perfusion and diffusion weighted imaging and dynamic contrast-enhanced MRI, including methods and software for measuring and modeling pharmacokinetics of imaging agents, including elimination, tissue delivery and clearance, receptor binding and enzyme activity. These principles will be applied to develop complementary optical imaging methods with conventional and activatable molecular probes. The practical aspects of animal models of human cancer, including human cell and tissue xenografts, transgenic cancer models, for molecular imaging will also be included as a necessary component of the training and research. The Candidate will be mentored in scientific writing, including submission of scientific manuscripts, as well as grantsmanship with the goal of at least one R01-level application submitted in year 4. This training will take place at Washington University School of Medicine, a world leader in biomedical research, particularly biomedical imaging. The Candidate will be mentored by and collaborate with outstanding researchers in the fields of optical imaging, magnetic resonance imaging and cancer biology. Optical imaging is an excellent method for low cost, high-throughput preclinical imaging using safe and stable contrast agents. Rather than radioactive contrast agents, optical imaging uses fluorescent compounds that can be visualized throughout the body for days to weeks after injection with no evident toxicity. Multiple agents injected separately or in the form of activatable agents can be detected throughout the body for days to weeks after injection with no evident toxicity. In the proposed work, fluorescent contrast agents will be investigated that target cancer-specific cell-surface receptors and extracellular enzymes. The expression of these biomarkers will be monitored in relation to therapeutic response to develop quantitative methods that can be used for preclinical drug development and eventually translated to clinical use. Optical imaging results will be compared and combined with diffusion-weighted and contrast-enhanced magnetic resonance imaging data for synergistic cancer characterization. The combined training and preclinical imaging research will equip the Candidate with the expertise and experience to be a leader in the field of preclinical imaging research. PUBLIC HEALTH RELEVANCE (provided by applicant): The Candidate will receive training in cancer biology and biomedical imaging techniques through development of multimodal imaging approach to measure therapeutic response in animal models of breast cancer. Detection of therapeutic response early initiation can speed the clinical decision- making process and improve overall response. Non-invasive imaging techniques are needed for this purpose.

描述(由申请人提供)：“临床前癌症模型中分子过程的定量光学成像”申请是为了响应NCRR项目宣布的病理学和比较医学特别强调研究职业奖(SERCA，K01)。越来越明显的是，没有一种单一的成像方式能够为诊断、预后和治疗效果提供足够的信息。应聘者寻求接受生物医学成像方面的培训，以领导独立的研究生涯，应用先进的光学成像方法和磁共振成像(MRI)来研究癌症的分子机制。具体的职业发展培训领域将包括涵盖癌症分子生物学、磁共振成像原理以及生物医学成像和造影剂开发原理的课程。使用肿瘤靶向荧光探针的分子成像原理，包括造影剂(小分子、大分子和纳米颗粒)和靶向部分(单抗、受体特异性蛋白、高亲和力多肽和可切割多肽序列)的特性。应聘者将接受关于磁共振成像的物理和生理学基础以及灌注和扩散加权成像和动态对比增强MRI的实验程序的指导，包括测量和模拟显像剂的药代动力学的方法和软件，包括消除、组织传递和清除、受体结合和酶活性。这些原理将被应用于开发与传统和可激活的分子探针互补的光学成像方法。人类癌症动物模型的实用方面，包括人类细胞和组织异种移植、用于分子成像的转基因癌症模型，也将作为培训和研究的必要组成部分包括在内。候选人将接受科学写作方面的指导，包括提交科学手稿，以及资质，目标是在第四年至少提交一份R01级申请。培训将在华盛顿大学医学院进行，该学院在生物医学研究，特别是生物医学成像方面处于世界领先地位。候选人将接受光学成像、磁共振成像和癌症生物学领域的杰出研究人员的指导和合作。光学成像是使用安全稳定的造影剂进行低成本、高通量临床前成像的一种极好的方法。光学成像使用的是荧光化合物，而不是放射性造影剂，注射后可以在体内观察几天到几周，没有明显的毒性。单独注射或以可激活剂的形式注射的多种药物在注射后几天至几周内可在全身检测到，没有明显的毒性。在这项拟议的工作中，将研究针对癌症特异性细胞表面受体和胞外酶的荧光造影剂。这些生物标志物的表达将根据治疗反应进行监测，以开发可用于临床前药物开发并最终转化为临床使用的定量方法。光学成像结果将与扩散加权和对比度增强的磁共振成像数据进行比较和组合，以协同确定癌症的特征。综合培训和临床前影像研究将使候选人具备成为临床前影像研究领域的领先者的专业知识和经验。 公共卫生相关性(由申请者提供)：应聘者将接受癌症生物学和生物医学成像技术方面的培训，通过开发多模式成像方法来测量乳腺癌动物模型的治疗反应。早期检测治疗反应可以加快临床决策过程，提高整体疗效。为此，需要非侵入性成像技术。